Letter by Virmani et al Regarding Article, “Drug-Eluting Stents in Animals and Patients: Where Do We Stand Today?”
To the Editor:
We read with interest Dr Drachman’s editorial1 on “Comparison of Inflammatory Response After Implantation of Sirolimus- and Paclitaxel-Eluting Stents in Porcine Coronary Arteries” by Wilson et al.2 We are concerned that Dr Drachmann gives the impression that animal models for preclinical testing before conducting human clinical trials provide relatively little information about the safety of drug-eluting stents and that human data thus far show no “additional risk of death or myocardial infarction, even in the most complex cases.” Wilson et al cautiously suggest that excessive inflammation, especially the extensive, granulomatous, eosinophil-rich reaction after deployment of Cypher stents (Cypher™, Cordis Corp., Miami Lakes, Fla), is a likely predictor of a similar reaction in humans, limited to the stented segment in both species. In pigs the reaction appears much more granulomatous, whereas in humans more often a diffuse vessel wall infiltration by T-lymphocytes and eosinophils is seen with this response, which has the characteristic features of a hypersensitivity reaction. Usually there is only a focal foreign body reaction with few, if any, eosinophils around stent struts in humans. Wilson et al document the occurrence of a diffuse granulomatous reaction almost exclusively in the Cypher-stented vessels, which was most marked at 90 and 180 days, with 39% showing a circumferential granulomatous reaction in all sections compared with 5% for Taxus (Taxus™, Boston Scientific, Natick, Mass). In almost all granulomas, esoinophil infiltration exceeded 10 cells per high power field. In a recent Circulation article,3 the numbers of eosinophils observed in the thrombus aspirates from late drug-eluting stent thrombosis were similar (ie, 34±28 eosinophils per high power field) in the patients with Cypher stents and late stent thrombosis, and these patients also showed positive remodeling by intravascular ultrasound. To our knowledge, a substantial hypersensitivity reaction is predominantly observed with the Cypher stent in humans and is supported by a body of evidence in living patients and at autopsy.3–5
Delayed healing documented in animals has also been seen in humans after deployment of Cypher and Taxus stents.6 Daemen et al previously showed that late stent thrombosis occurs at a rate of 0.6%/yr for at least 3 years, and it may continue for even longer periods.7 The issue of the safety of the “off-label” use of drug-eluting stents continues to be hotly debated. It seems likely that randomized clinical trials to examine the safety of such uses are needed before stating that drug-eluting stents pose no additional risk.
In conclusion, we believe the animal data presented by Wilson et al, together with the clinical data in the literature, may be predictive of a local hypersensitivity reaction in humans, although its prevalence may be much lower than in pigs. We need to be cautious in disregarding pathological findings in animals, especially inflammatory reactions, as not being representative of similar untoward effects in humans.
Dr Virmani has received company-sponsored research support from Medtronic AVE, Abbott Vascular, W.L. Gore, Atrium Medical Corp, Boston Scientific, NDC Cordis Corp, Novartis, Orbus Neich Medical Inc, Biotronik, BioSensors, Alchimedics Medical, and Terumo. Dr Virmani has also served as a consultant to Medtronic AVE, Abbott Laboratories, W.L. Gore, Terumo, and Volcano Therapeutics Inc. Dr Wilson is a paid consultant for Boston Scientific but has no financial interests. Dr Finn has a sponsored research agreement with Boston Scientific.
Drachman DE. Drug-eluting stents in animals and patients: where do we stand today? Circulation. 2009; 120: 101–103.
Wilson GJ, Nakazawa G, Schwartz RS, Huibregtse B, Poff B, Herbst TJ, Baim DS, Virmani R. Comparison of inflammatory response after implantation of sirolimus- and paclitaxel-eluting stents in porcine coronary arteries. Circulation. 2009; 120: 141–149.
Cook S, Ladich E, Nakazawa G, Eshtehardi P, Neidhart M, Vogel R, Togni M, Wenaweser P, Billinger M, Seiler C, Gay S, Meier B, Pichler WJ, Juni P, Virmani R, Windecker S. Correlation of intravascular ultrasound findings with histopathological analysis of thrombus aspirates in patients with very late drug-eluting stent thrombosis. Circulation. 2009; 120: 391–399.
Virmani R, Guagliumi G, Farb A, Musumeci G, Grieco N, Motta T, Mihalcsik L, Tespili M, Valsecchi O, Kolodgie FD. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: should we be cautious? Circulation. 2004; 109: 701–705.
Daemen J, Wenaweser P, Tsuchida K, Abrecht L, Vaina S, Morger C, Kukreja N, Juni P, Sianos G, Hellige G, van Domburg RT, Hess OM, Boersma E, Meier B, Windecker S, Serruys PW. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large 2-institutional cohort study. Lancet. 2007; 369: 667–678.